Skip to main content

Advertisement

SpringerLink
Log in

Effects of an alpha-1d adrenoreceptor antagonist (naftopidil) on bladder dysfunction after radiotherapy in female rats

  • Original Article
  • Published:
International Urogynecology Journal Aims and scope Submit manuscript

Abstract

Purpose

Storage-phase bladder dysfunction can develop after pelvic radiotherapy. As the alpha-1d adrenoreceptor (a1d-AR) is dominant in the human detrusor, we aimed to investigate the effect of an a1d-AR antagonist on bladder dysfunction after pelvic radiotherapy in a rat model.

Materials and methods

Twenty-four female Wistar rats were used. Eight rats (14–15 weeks, 250–300 g) were randomized to three groups (normal reference group, radiation alone group and radiation plus naftopidil group). An 18-Gy dose of radiotherapy was applied to the radiation alone and radiation plus naftopidil groups. Naftopidil (20 mg/kg) was administered daily to the radiation plus naftopidil group. Four weeks after radiation, all rats underwent cystometry and were killed for reverse transcription polymerase chain reaction to detect mRNAs [a1d-AR, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF)], Western blot to detect proteins (a1d-AR, extracellular-signal-regulated kinase, BDNF and VEGF) and immunohistochemistry.

Results

Compared to the radiation alone group, (1) the decrease in the mRNA and protein expression of a1d-AR and VEGF was ameliorated, (2) the increase in the expression of BDNF mRNA and proteins such as extracellular-signal-regulated kinase and BDNF was suppressed, (3) submucosal thickness and vascularity on immunohistochemistry were improved, and (4) the baseline intravesical pressure and intercontraction interval in cystometry were ameliorated in the radiation plus naftopidil group.

Conclusion

Administration of an a1d-AR antagonist could improve storage-phase bladder dysfunction after radiotherapy not only by upregulating a1d-AR, which might decrease bladder compliance, but also by enhancing vascularity, which might protect the urinary bladder from chronic ischemic inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Katepratoom C, Manchana T, Amornwichet N. Lower urinary tract dysfunction and quality of life in cervical cancer survivors after concurrent chemoradiation versus radical hysterectomy. Int Urogynecol J. 2014;25:91–6. https://doi.org/10.1007/s00192-013-2151-6.

    Article  PubMed  Google Scholar 

  2. Lepor H, Baumann M, Shapiro E. The alpha adrenergic binding properties of terazosin in the human prostate adenoma and canine brain. J Urol. 1988;140:664–7. https://doi.org/10.1016/s0022-5347(17)41751-4.

    Article  CAS  PubMed  Google Scholar 

  3. Nasu K, Moriyama N, Kawabe K, et al. Quantification and distribution of alpha 1-adrenoceptor subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and non-hypertrophied tissue. Br J Pharmacol. 1996;119:797–803. https://doi.org/10.1111/j.1476-5381.1996.tb15742.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Malloy BJ, Price DT, Price RR, et al. Alpha1-adrenergic receptor subtypes in human detrusor. J Urol. 1998;160:937–43. https://doi.org/10.1097/00005392-199809010-00092.

    Article  CAS  PubMed  Google Scholar 

  5. Schwinn D, Price DT, Narayan P. α1-Adrenoceptor subtype selectivity and lower urinary tract symptoms. Mayo Clin Proc. 2004;79:1423–34. https://doi.org/10.4065/79.11.1423.

    Article  CAS  PubMed  Google Scholar 

  6. Sugaya K, Nishijima S, Miyazato M, et al. Effects of intrathecal injection of tamsulosin and naftopidil, alpha-1A and -1D adrenergic receptor antagonists, on bladder activity in rats. Neurosci Lett. 2002;328:74–6. https://doi.org/10.1016/s0304-3940(02)00459-7.

    Article  CAS  PubMed  Google Scholar 

  7. Hara N, Mizusawa T, Obara K, Takahashi K. The role of naftopidil in the management of benign prostatic hyperplasia. Ther Adv Urol. 2013;5:111–9. https://doi.org/10.1177/1756287212461681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nishino Y, Masue T, Miwa K, et al. Comparison of two alpha1-adrenoceptor antagonists, naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary tract symptoms with benign prostatic hyperplasia: a randomized crossover study. BJU Int. 2006;97:747–51, discussion 51. https://doi.org/10.1111/j.1464-410X.2006.06030.x.

    Article  CAS  PubMed  Google Scholar 

  9. Yamaguchi S, Osanai H, Numata A, et al. alpha1D/A-adrenoceptor antagonist naftopidil for the male lower urinary tract symptoms associated with benign prostatic hyperplasia: efficacy of dose increase therapy. Int J Urol. 2013;20:513–9. https://doi.org/10.1111/j.1442-2042.2012.03188.x.

    Article  CAS  PubMed  Google Scholar 

  10. Takeda M, Homma Y, Araki I, et al. Predictive factors for the effect of the alpha1-D/a adrenoceptor antagonist naftopidil on subjective and objective criteria in patients with neurogenic lower urinary tract dysfunction. BJU Int. 2011;108:100–7. https://doi.org/10.1111/j.1464-410X.2010.09682.x.

    Article  CAS  PubMed  Google Scholar 

  11. Hampel C, Dolber PC, Smith MP, et al. Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction. J Urol. 2002;167:1513–21. https://doi.org/10.1016/S0022-5347(05)65355-4.

    Article  CAS  PubMed  Google Scholar 

  12. Dmitrieva N, Zhang G, Nagabukuro H. Increased alpha1D adrenergic receptor activity and protein expression in the urinary bladder of aged rats. World J Urol. 2008;26:649–55. https://doi.org/10.1007/s00345-008-0292-x10.1007/s00345-008-0292-x.

    Article  CAS  PubMed  Google Scholar 

  13. Lee G, Park H, Park SH, Lee JG. Modulation of alpha 1 adrenergic receptors on urinary bladder in rat spinal cord injury model. Int Neurourol J. 2012;16:62–8. https://doi.org/10.5213/inj.2012.16.2.62.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Majima T, Yamamoto T, Funahashi Y. Effect of Naftopidil on bladder microcirculation in a rat model of bladder outlet obstruction. LUTS. 2017;9:111–6. https://doi.org/10.1111/luts.12119.

    Article  CAS  PubMed  Google Scholar 

  15. Ochodnicky P, Cruz CD, Yoshimura N, et al. Neurotrophins as regulators of urinary bladder function. Nat Rev Urol. 2012;9:628–37. https://doi.org/10.1038/nrurol.2012.178.

    Article  CAS  PubMed  Google Scholar 

  16. Jiang HH, Song QX, Gill BC, et al. Electrical stimulation of the pudendal nerve promotes neuroregeneration and functional recovery from stress urinary incontinence in a rat model. Am J Physiol Renal Physiol. 2018;315:F1555–F64. https://doi.org/10.1152/ajprenal.00431.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Deng Z, Sui G, Rosa PM, Zhao W. Radiation-induced c-Jun activation depends on MEK1-ERK1/2 Signaling pathway in microglial cells. PLoS One. 2012;7:e36739. https://doi.org/10.1371/journal.pone.0036739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kilkenny C, Browne WJ, Cuthill IC, et al. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412. https://doi.org/10.1371/journal.pbio.1000412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Okazaki S, Murata K, Noda SE, et al. Dose-volume parameters and local tumor control in cervical cancer treated with central-shielding external-beam radiotherapy and CT-based image-guided brachytherapy. J Radiat Res. 2019;60:490–500. https://doi.org/10.1093/jrr/rrz023.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Toita T, Kakinohana Y, Ogawa K, et al. Combination external beam radiotherapy and high-dose-rate intracavitary brachytherapy for uterine cervical cancer: analysis of dose and fractionation schedule. Int J Radiat Oncol Biol Phys. 2003;56:1344–53. https://doi.org/10.1016/s0360-3016(03)00288-8.

    Article  PubMed  Google Scholar 

  21. Fowler JF. 21 years of biologically effective dose. Br J Radiol. 2010;83:554–68. https://doi.org/10.1259/bjr/31372149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol. 1989;62:679–94. https://doi.org/10.1259/0007-1285-62-740-679.

    Article  CAS  PubMed  Google Scholar 

  23. Institutional Animal Care and Use Committee. Anesthesia (Guideline). 2019. https://animal.research.uiowa.edu/iacuc-guidelines-anesthesia. Accessed Nov 19 2019.

  24. Yamashita S, Katsumata O. Heat-induced antigen retrieval in immunohistochemistry: mechanisms and applications. Methods Mol Biol. 2017;1560:147–61. https://doi.org/10.1007/978-1-4939-6788-9_10.

    Article  CAS  PubMed  Google Scholar 

  25. Lee DS, Kim SJ. Kwon EB, et al comparison of in vivo biocompatibilities between parylene-C and polydimethylsiloxane for implantable microelectronic devices. Bull Mater Sci. 2013;36:1127–32 https://www.ias.ac.in/public/Volumes/boms/036/06/1127-1132.pdf.

    Article  CAS  Google Scholar 

  26. Elrashidy RA, Liu G. Long-term diabetes causes molecular alterations related to fibrosis and apoptosis in rat urinary bladder. Exp Mol Pathol. 2019;111:104304. https://doi.org/10.1016/j.yexmp.2019.104304.

    Article  CAS  PubMed  Google Scholar 

  27. Lee JY, Park JM, Na YG, et al. Expression of bladder α1-adrenoceptor subtype after relief of partial bladder outlet obstruction in a rat model. Investig Clin Urol. 2020;61:297–303. https://doi.org/10.4111/icu.2020.61.3.297.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Park MG, Park HS, Lee JG, Kim HJ. Changes in awake Cystometry and expression of bladder β-adrenoceptors after partial bladder outlet obstruction in male rats. Int Neurourol J. 2010;14:157–63. https://doi.org/10.5213/inj.2010.14.3.157.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Festing MF. Design and statistical methods in studies using animal models of development. ILAR J. 2006;47:5–14. https://doi.org/10.1093/ilar.47.1.5.

    Article  CAS  PubMed  Google Scholar 

  30. Kojima Y, Sasaki S, Kubota Y, et al. Up-regulation of alpha1a and alpha1d-adrenoceptors in the prostate by administration of subtype selective alpha1-adrenoceptor antagonist tamsulosin in patients with benign prostatic hyperplasia. J Urol. 2011;186:1530–6. https://doi.org/10.1016/j.juro.2011.05.048.

    Article  CAS  PubMed  Google Scholar 

  31. Lepor H. Long-term evaluation of Tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Tamsulosin Invest Group Urol. 1998;51:901–6. https://doi.org/10.1016/s0090-4295(98)00127-7.

    Article  CAS  Google Scholar 

  32. Smit SG, Heyns CF. Management of radiation cystitis. Nat Rev Urol. 2010;7:206–14. https://doi.org/10.1038/nrurol.2010.23.

    Article  PubMed  Google Scholar 

  33. Ikeda Y, Zabbarova IV, Birder LA, et al. Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice. Neurourol Urodyn. 2018;37:2441–51. https://doi.org/10.1002/nau.23721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sekerci CA, Tanidir Y, Toprak T, et al. Value of urinary brain-derived neurotrophic factor levels on the assessment of botulinum toxin type a treatment for neurogenic detrusor overactivity in children with myelodysplasia. J Urol. 2019;201:174–80. https://doi.org/10.1016/j.juro.2018.06.065.

    Article  PubMed  Google Scholar 

  35. Minet E, Arnould T, Michel G, et al. ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett. 2000;468:53–8. https://doi.org/10.1016/s0014-5793(00)01181-9.

    Article  CAS  PubMed  Google Scholar 

  36. Perez-Aso M, Segura V, Montó F, et al. The three α1-adrenoceptor subtypes show different spatio-temporal mechanisms of internalization and ERK1/2 phosphorylation. Biochim Biophys Acta. 1833;2013:2322–33. https://doi.org/10.1016/j.bbamcr.2013.06.013.

    Article  CAS  Google Scholar 

  37. Hague C, Gonzalez-Cabrera PJ, Jeffries WB, Abel PW. Relationship between α1-adrenergic receptor-induced contraction and extracellular signal-regulated kinase activation in the bovine inferior alveolar artery. J Pharmacol Exp Ther. 2002;303:403–11. https://doi.org/10.1124/jpet.102.037531.

    Article  CAS  PubMed  Google Scholar 

  38. Yamamoto H, Rundqvist H, Branco C, et al. Autocrine VEGF isoforms differentially regulate endothelial cell behavior. Front Cell Dev Biol. 2016;4:99. https://doi.org/10.3389/fcell.2016.00099.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Golubeva AV, Zhdanov AV, Mallel G, et al. The mouse cyclophosphamide model of bladder pain syndrome: tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors. Physiol Rep. 2014;2:e00260. https://doi.org/10.1002/phy2.260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gordon IO, Agrawal N, Willis E, et al. Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation. Aliment Pharmacol Ther. 2018;47:922–39. https://doi.org/10.1111/apt.14526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are particularly grateful to Jong-Hoon Lee in the Department of Radiation Oncology for providing us with the opportunity to perform this study. We are also grateful to Inae Park (Department of Urology, St. Vincent’s Hospital) and Eun Yong Shin (The Institute of Medical Science, St. Vincent’s Hospital) for assisting with all of the experiments. This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C2915) and by a grant from Korea Research Foundation for Gynecologic Cancer.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Sung Jong Lee

  2. Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Sung Jong Lee

  3. Department of Urology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 93, Jungbu-daero, Paldal-gu, Suwon-si, Gyeonggi-do, 16247, Republic of Korea

    Hee Youn Kim & Dong Sup Lee

Authors
  1. Sung Jong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hee Youn Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dong Sup Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Protocol/project development: DS Lee; Data collection: DS Lee and HY Kim; Data analysis: SJ Lee and DS Lee; Manuscript writing/editing: SJ Lee and DS Lee; Performing experiment: DS Lee and HY Kim.

Corresponding author

Correspondence to Dong Sup Lee.

Ethics declarations

All experimental protocols were approved by the Institutional Animal Care and Use Committee of St. Vincent’s Hospital, The Catholic University of Korea (approval no. IACUC 17-1; date: 26 January 2017).

Conflicts of interest

None.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PNG 306 kb)

High-resolution image (TIF 46 kb)

ESM 2

(DOC 30 kb)

ESM 3

(DOC 30 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, S.J., Kim, H.Y. & Lee, D.S. Effects of an alpha-1d adrenoreceptor antagonist (naftopidil) on bladder dysfunction after radiotherapy in female rats. Int Urogynecol J 32, 2747–2755 (2021). https://doi.org/10.1007/s00192-020-04472-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00192-020-04472-5

Keywords

Search

Navigation